This competitive renewal extends the successful work (35 published papers) funded under 5R01GM076692-01 Multiscale Studies of Segmentation in Vertebrate Embryos to develop multiscale simulation tools for the simulation of somite formation in chicken. The strategic context of the current proposal is to unify the multiple accomplishments achieved during the original funding period into a coherent model of somitogenesis and to deliver the primary recommendation of the NIH-led Interagency Modeling and Analysis Group (IMAG) Miniworkshop and Principal Investigator's Meeting on Model Sharing, April 11-12, 2007: "a focused demonstration project for multiscale simulation techniques, which addresses a well- defined, specific problem in developmental biology, which includes a variety of biological mechanisms of importance throughout development and for which a unified multiscale approach is essential." Chick somitogenesis is an excellent choice of demonstration project because it is well- characterized experimentally, requires simulation of most fundamental developmental mechanisms, and requires both the unification of existing methodologies at multiple scales (in this case merging the widely-employed, open-source software packages Systems Biology Workbench (SBW) for subcellular modeling and CompuCell3D (CC3D) for multicell modeling into a Tissue-Simulation Environment (TSE)) and the development of a number of key additional software components of broad utility in developmental-biology simulation and in critical biomedical areas such as cancer and vascular research. This proposal leverages the investment NIGMS has recently made in software infrastructure development under 1R01GM077138-01A1 to Glazier and 1R01GM081070-01A1 to Sauro, which, while they greatly increase the scope of CC3D and SBW separately (by supporting improved user interfaces for model generation, execution and analysis;enhanced scripting- language support, development of testing and validation modules, improving documentation, training materials and user support), do not cover the development or parallelization of a merged SBW/CC3D, or the deployment of a biologically-meaningful demonstration project. PUBLIC HEALTH RELEVANCE: Simulations of cell interactions and underlying molecular mechanisms during embryonic development can play a vital role in experimental biomedical research, help with the interpretation of experimental results, suggest experiments, predict experimental outcomes and lead to a deeper understanding of fundamental biological mechanisms, thus expediting the understanding of diseases and the development of treatment strategies. Successful completion of the presented research plan will improve the involvement of medical institutions and industry, and their interaction in the development of modeling tools and their effective use in the creation of novel drugs and treatments.